15. Section for Studies on Metastasis

In 1996, three subjects were investigated: 1) development of an antisense K-ras RNA strategy for pancreatic cancer, 2) evaluation of tissue specific promoters for targeting therapeutic gene expression, and 3) study of the factors which may be involved in the osteogenic metastasis of prostate cancer.

Specificity of K-ras Antisense Therapy

We reported that antisense expression of the 347-bp wild-type K-ras cDNA fragment containing exons 1 and 2 caused growth suppression of the human pancreatic cancer cell line AsPC-1.⁽¹⁶⁴⁾ The antisense K-ras RNA strategy was tested for six additional pancreatic cancer cell lines. Four with the K-ras mutation showed significant growth suppression, while the response to the antisense K-ras RNA was marginal to nil in the other three cell lines without the mutation. The degree of the K-ras p21 protein down-regulation was comparable, 30-50% of that in parental cells, irrespective of K-ras mutation status, except in the K-ras mutation-negative cell line, BxPC-3, which showed no decrease in p21 expression. One plausible explanation is that the pancreatic cancer cells with the K-ras mutation depend strictly on the continued expression of the abnormal K-ras protein, while the cells without a K-ras abnormality show more tolerance regarding the level of the K-ras p21 protein, suggesting the possibility of "biological targeting" by this strategy.

Targeting Gene Expression

Angiogenesis is a potential target of cancer gene therapy, because neo-vascularization is infrequent in normal adult physiology. Of the putative von Willebrand factor (vWf) promoter sequences, the -487/+247 induced suicidal activity preferentially in human umbilical vein endothelial cells.⁽¹⁶⁵⁾ Combination with the CMV enhancer sequence increased vWf promoter activity without significant loss of tissue specificity.

Cloning and Expression Analysis of BMPR-IB

Bone morphogenetic protein (BMP) is a strong bone-inducing factor. The functional BMP receptor (BMPR) consists of a heterodimer of the type I and II receptors. Human BMP receptor (BMPR)-IB cDNA was cloned, and RNA blot analysis showed that BMPR-IB expression is highest in the prostate, exceeding that of all other major human organs.

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